4d8a

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==Crystal structure of B. anthracis DHPS with compound 21==
==Crystal structure of B. anthracis DHPS with compound 21==
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<StructureSection load='4d8a' size='340' side='right' caption='[[4d8a]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
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<StructureSection load='4d8a' size='340' side='right'caption='[[4d8a]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4d8a]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bacillus_anthracis Bacillus anthracis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D8A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D8A FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4d8a]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_anthracis_str._A2012 Bacillus anthracis str. A2012]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D8A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D8A FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0HY:METHYL+(3R)-3-(7-AMINO-4,5-DIOXO-1,4,5,6-TETRAHYDROPYRIMIDO[4,5-C]PYRIDAZIN-3-YL)BUTANOATE'>0HY</scene>, <scene name='pdbligand=LYS:LYSINE'>LYS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.183&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tws|1tws]], [[4d8z|4d8z]], [[4d9p|4d9p]], [[4daf|4daf]], [[4dai|4dai]], [[4db7|4db7]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0HY:METHYL+(3R)-3-(7-AMINO-4,5-DIOXO-1,4,5,6-TETRAHYDROPYRIMIDO[4,5-C]PYRIDAZIN-3-YL)BUTANOATE'>0HY</scene>, <scene name='pdbligand=LYS:LYSINE'>LYS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">folP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1392 Bacillus anthracis])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4d8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d8a OCA], [https://pdbe.org/4d8a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d8a RCSB], [https://www.ebi.ac.uk/pdbsum/4d8a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d8a ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydropteroate_synthase Dihydropteroate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.15 2.5.1.15] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4d8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d8a OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d8a RCSB], [http://www.ebi.ac.uk/pdbsum/4d8a PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/Q81VW8_BACAN Q81VW8_BACAN]
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Dihydropteroate synthase (DHPS) is the validated drug target for sulfonamide antimicrobial therapy. However, due to widespread drug resistance and poor tolerance, the use of sulfonamide antibiotics is now limited. The pterin binding pocket in DHPS is highly conserved and is distinct from the sulfonamide binding site. It therefore represents an attractive alternative target for the design of novel antibacterial agents. We previously carried out the structural characterization of a known pyridazine inhibitor in the Bacillus anthracis DHPS pterin site and identified a number of unfavorable interactions that appear to compromise binding. With this structural information, a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines were designed to improve binding affinity. Most importantly, the N-methyl ring substitution was removed to improve binding within the pterin pocket, and the length of the side chain carboxylic acid was optimized to fully engage the pyrophosphate binding site. These inhibitors were synthesized and evaluated by an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic, and thermodynamic perspectives. This study clearly demonstrates that compounds lacking the N-methyl substitution exhibit increased inhibition of DHPS, but the beneficial effects of optimizing the side chain length are less apparent.
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Structure-Based Design of Novel Pyrimido[4,5-c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity.,Zhao Y, Hammoudeh D, Yun MK, Qi J, White SW, Lee RE ChemMedChem. 2012 Mar 13. doi: 10.1002/cmdc.201200049. PMID:22416048<ref>PMID:22416048</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Dihydropteroate synthase|Dihydropteroate synthase]]
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*[[Dihydropteroate synthase 3D structures|Dihydropteroate synthase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Bacillus anthracis]]
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[[Category: Bacillus anthracis str. A2012]]
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[[Category: Dihydropteroate synthase]]
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[[Category: Large Structures]]
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[[Category: Hammoudeh, D]]
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[[Category: Hammoudeh D]]
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[[Category: Lee, R E]]
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[[Category: Lee RE]]
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[[Category: White, S W]]
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[[Category: White SW]]
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[[Category: Synthase]]
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[[Category: Tim barrel]]
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[[Category: Tim narrel]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Crystal structure of B. anthracis DHPS with compound 21

PDB ID 4d8a

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